Transcript Pharmaceutical suspension

Pharmaceutical suspension
Dr. Nd. Harun Ar Rashid
Pharmacy, NUB
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Definition
• A Pharmaceutical suspension is a coarse dispersion in
which internal phase is dispersed uniformly throughout the
external phase.
• The internal phase consisting of insoluble solid
particles having a specific range of size which is maintained
uniformly throughout the suspending vehicle with aid of
single or combination of suspending agent.
• The external phase (suspending medium) is generally
aqueous in some instance, may be an organic or oily liquid for
non oral use.
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Classification
• Based On General Classes
Oral suspension
Externally applied suspension
Parenteral suspension
• Based On Proportion Of Solid Particles
Dilute suspension (2 to10%w/v solid)
Concentrated suspension (50%w/v solid)
• Based On Electrokinetic Nature Of Solid Particles
Flocculated suspension
Deflocculated suspension
•
Based On Size Of Solid Particles
Colloidal suspension (< 1 micron)
Coarse suspension (>1 micron)
Nano suspension (10 ng)
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Advantages
• Suspension can improve chemical stability of certain drug. E.g.
Procaine penicillin G
• Drug in suspension exhibits higher rate of bioavailability than other
dosage forms. bioavailability is in following order,
•
Solution > Suspension > Capsule > Compressed Tablet > Coated
tablet
• Duration and onset of action can be controlled. E.g. Protamine ZincInsulin suspension
• Suspension can mask the unpleasant/ bitter taste of drug. E.g.
Chloramphenicol palmitate
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Disadvantages
•
Physical stability, sedimentation and compaction can
causes problems.
•
It is bulky sufficient care must be taken during handling and
transport.
•
It is difficult to formulate
• Uniform and accurate dose can not be achieved unless
suspension are packed in unit dosage form
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Features Desired In Pharmaceutical Suspensions
• The suspended particles should not settle rapidly and
sediment produced, must be easily re-suspended by the use
of moderate amount of shaking.
• It should be easy to pour yet not watery and no grittiness.
• It should have pleasing odour, colour and palatability.
• Good syringeability.
• It should be physically, chemically and microbiologically
stable.
• Parenteral/ophthalmic suspension should be sterilizable.
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Applications
•
Suspension is usually applicable for drug which is insoluble or poorly soluble. E.g.
Prednisolone
•
suspension To prevent degradation of drug or to improve stability of drug. E.g.
Oxytetracycline suspension
•
To
mask
the
taste
of
bitter
of
unpleasant
drug.
E.g. Chloramphenicol palmitate suspension
•
Suspension of drug can be formulated for topical application e.g. Calamine lotion.
•
Suspension can be formulated for parentral application in order to control rate of
drug absorption, E.g. penicillin procaine
•
Vaccines as a immunizing agent are often formulated as suspension.
E.g. Cholera vaccine
•
X-ray
contrast
agent
are
also
formulated
E.g. Barium sulphate for examination of alimentary tract
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as
suspension.
Theory of Suspensions
• Sedimentation Behaviour
• Sedimentation means settling of particle or floccules
occur under gravitational force in liquid dosage form.
• Theory of Sedimentation
• Velocity of sedimentation expressed by Stoke’s equation
• V= 2r2 (ρ s- ρ o ) g or V= d2 (ρ s- ρ o ) g
•
9
18
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•
•
•
•
•
•
•
Where, vsed. = sedimentation velocity in cm / sec
d = Diameterof particle
r = radius of particle
ρ s= density of disperse phase
ρ o= density of disperse media
g = acceleration due to gravity
η = viscosity of disperse medium in poise
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• Factors Affecting Sedimentation
• Particle size diameter (d)
• Vαd2
• Sedimentation velocity (v) is directly proportional to the square of diameter
of particle.
• Density difference between dispersed phase and dispersion media (ρs - ρo)
• V α (ρ s - ρo)
• Generally, particle density is greater than dispersion medium but, in certain
cases particle density is less than dispersed phase, so suspended particle
floats & is difficult to distribute uniformly in the vehicle.
• If density of the dispersed phase and dispersion medium are equal, the rate
of settling becomes zero.
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• Viscosity of dispersion medium (η )
V α 1/ ηo
• Sedimentation velocity is inversely proportional to
viscosity of dispersion medium.
• So increase in viscosity of medium, decreases settling, so the
particles achieve good dispersion system but greater increase
in viscosity gives rise to problems like pouring, syringibility
and redispersibility of suspensoin.
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• Advantages and Disadvantages due to viscosity of medium
Advantages
• High viscosity inhibits the crystal growth.
• High viscosity prevents the transformation of metastable
crystal to stable crystal.
• High viscosity enhances the physical stability.
Disadvantages
• High viscosity hinders the re-dispersibility of the sediments
• High viscosity retards the absorption of the drug.
• High viscosity creates problems in handling of the material
during manufacturing.
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I- Sedimentation Parameters
Two important parameters are considered:
•
•
•
•
•
Sedimentation volume (F) or height (H) for flocculated suspensions
F = V u / VO -------------- (A)
Where, Vu = final or ultimate volume of sediment
VO = original volume of suspension before settling.
Sedimentation volume is a ratio of the final or
ultimate volume of sediment (Vu) to the original volume of sediment
(VO) before settling.
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• Sedimentation volume can have values ranging from less than
1 to greater than1; F is normally less than 1.
• F=1,such product is said to be in flocculation equilibrium, and
show no clear supernatant on standing
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Fig.1: Suspensions quantified by sedimentation volume (f)
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• Degree of flocculation (β)
• It is a very useful parameter for flocculation
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The Sedimentation Behavior of Flocculated and Deflocculated
Suspensions:
Flocculated Suspensions
In flocculated suspension, formed flocks (loose aggregates)
will cause increase in sedimentation rate due to increase in
size of sedimenting particles. Hence, flocculated suspensions
sediment more rapidly.
• Here, the sedimentation depends not only on the size of the
flocs but also on the porosity of flocks. In flocculated
suspension the loose structure of the rapidly sedimenting
flocs tends to preserve in the sediment, which contains an
appreciable amount of entrapped liquid. The volume of final
sediment is thus relatively large and is easily redispersed by
agitation.
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Fig 2: Sedimentation behaviour of flocculated and deflocculated suspensions
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Deflocculated suspensions
• In deflocculated suspension, individual particles are settling,
so rate of sedimentation is slow which prevents entrapping of
liquid medium which makes it difficult to re-disperse by
agitation.
• This phenomenon also called ‘cracking’ or ‘claying’. In
deflocculated suspension larger particles settle fast and
smaller remain in supernatant liquid so supernatant
appears cloudy whereby in flocculated suspension, even the
smallest particles are involved in flocs, so the supernatant
does not appear cloudy.
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• Flocculating Agents
Flocculating agents decreases zeta potential of the
suspended charged particle and thus cause
aggregation (flock formation) of the particles.
• Examples of flocculating agents are:
• Neutral electrolytes such as KCl, NaCl.
• Surfactants
• Polymeric flocculating agents
• Sulfate, citrates, phosphates salts
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• Neutral electrolytes e.g. NaCl, KCl besides acting as
flocculating agents, also decreases interfacial tension of the
surfactant solution. If the particles are having less surface
charge then monovalent ions are sufficient to cause
flocculation e.g. steroidal drugs.
• For highly charged particles e.g. insoluble polymers and polyelectrolytes species, di or trivalent flocculating agents are
used.
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• Method of Floccules Formation
• The different methods used to form floccules are mentioned
below:
• 1 . Electrolytes
• Electrolytes decrease electrical barrier between the particles
and bring them together to form floccules. They reduce zeta
potential near to zero value that results in formation of bridge
between adjacent particles, which lines them together in a
loosely arranged structure.
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• If we disperse particles of bismuth subnitrate in water we find
that based on electrophoretic mobility potential because of
the strong force of repulsion between adjacent particles, the
system is peptized or deflocculated. By preparing series of
bismuth subnitrate suspensions containing increasing
concentration of monobasic potassium phosphate co-relation
between apparent zeta potential and sedimentation volume,
caking,
and
flocculation
can
be
demonstrated.
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Fig 3: Caking diagram, showing the flocculation of a bismuth subnitrate
suspension by means of the flocculating agent.
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• The addition of monobasic potassium phosphate to the
suspended bismuth subnitrate particles causes the positive
zeta potential to decrease owing to the adsorption of
negatively charged phosphate anion.
• With continued addition of the electrolyte, the zeta potential
eventually falls to zero and then increases in negative
directions.
• Only when zeta potential becomes sufficiently negative to
affect potential does the sedimentation volume start to fall.
• Finally, the absence of caking in the suspensions correlates
with the maximum sedimentation volume, which, as stated
previously, reflects the amount of flocculation.
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2.
Surfactants
•
Both ionic and non-ionic surfactants can be used to bring
about flocculation of suspended particles.
 Optimum concentration is necessary because these
compounds also act as wetting agents to achieve dispersion.
 Optimum concentrations of surfactants bring down the
surface free energy by reducing the surface tension between
liquid medium and solid particles. This tends to form closely
packed agglomerates.
 The particles possessing less surface free energy are
attracted towards to each other by van der-waals forces and
forms loose agglomerates.
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3. Polymers
Polymers possess long chain in their structures.
Starch, alginates, cellulose derivatives, carbomers, tragacanth
The part of the long chain is adsorbed on the surface of the
particles and remaining part projecting out into the dispersed
medium.
Bridging between these later portions, also leads to the
formation of flocs.
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• Viscosity of Suspensions
Viscosity of suspensions is of great importance for stability and pourability
of suspensions. As we know suspensions have least physical stability
amongst all dosage forms due to sedimentation and cake formation.
• So as the viscosity of the dispersion medium increases, the terminal settling
velocity decreases thus the dispersed phase settle at a slower rate and they
remain dispersed for longer time yielding higher stability to the suspension.
• On the other hand as the viscosity of the suspension increases, it’s
pourability decreases and inconvenience to the patients for dosing
increases.
• Thus, the viscosity of suspension should be maintained within optimum
range to yield stable and easily pourable suspensions.
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• Different Approaches To Increase The Viscosity of Suspensions
• Various approaches have been suggested to enhance the
viscosity of suspensions. Few of them are as follows:
• 1. Viscosity Enhancers
• Some natural gums (acacia, tragacanth), cellulose derivatives
(sodium CMC, methyl cellulose), clays(bentonite, veegum),
carbomers, colloidal silicon dioxide (Aerosil), and sugars
(glucose, fructose) are used to enhance the viscosity of the
dispersion medium. They are known as suspending agents.
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• List of Suspending Agents
•
•
•
•
•
•
•
•
•
•
•
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Alginates
Methylcellulose
Hydroxyethylcellulose
Carboxymethylcellulose
Sodium Carboxymethylcellulose
Microcrystalline cellulose
Acacia, Tragacanth, Xanthan gum
Bentonite
Carbomer
Powdered cellulose
Gelatin
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• 2. Co-solvents
• Some solvents which themselves have high viscosity are used
as co-solvents to enhance the viscosity of dispersion medium:
• Glycerol, propylene glycol, sorbitol.
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• Most suspending agents perform two functions i.e. besides
acting as a suspending agent they also imparts viscosity to the
solution. Suspending agents form film around particle and
decrease interparticle attraction.
• A good suspension should have well developed
thixotropy.
• At rest the solution is sufficient viscous to prevent
sedimentation and thus aggregation or caking of the particles.
When agitation is applied the viscosity is reduced and provide
good flow characteristic from the mouth of bottle.
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• Thixotropy
• Thixotropy
is
defined
as
the
isothermal
slow reversible conversion of gel to sol. Thixotropic
substances on applying shear stress convert to sol(fluid) and
on
standing
they
slowly
turn
to
gel
(semisolid).
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• Other Formulation Aspects
• Introduciton
• A perfect suspension is one, which provides content uniformity. The
formulator must encounter important problems regarding particle size
distribution, specific surface area, inhibition of crystal growth and changes
in the polymorphic form. The formulator must ensure that these and
other properties should not change after long term storage and do not
adversely affect the performance of suspension.
• Choice of pH, particle size, viscosity, flocculation, taste, color and odor
are some of the most important factors that must be controlled at the
time of formulation.
• Formulation Components
The various components, which are used in suspension formulation, are
as follows.
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 Components
Function
API
Active drug substances
Wetting agents
They are added to disperse solids in continuous
liquid phase.
Flocculating agents
They are added to floc the drug particles
Thickeners
They are added to increase the viscosity of
suspension.
Buffers
They are added to stabilize the suspension to a
and pH adjusting agents
desired pH range.
Osmotic agents
They are added to adjust osmotic pressure
comparable to biological fluid.
Coloring agents
They are added to impart desired color to
suspension and improve elegance.
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Preservatives
They are added to prevent microbial growth.
External liquid vehicle
They are added to construct structure of the final
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suspension.
• Wetting
Agents
Hydrophilic materials are easily wetted by water while hydrophobic
materials are not. However hydrophobic materials are easily wetted by
non-polar liquids. The extent of wetting by water is dependent on the
hydrophillicity of the materials. If the material is more hydrophilic it finds
less difficulty in wetting by water. Inability of wetting reflects the higher
interfacial tension between material and liquid. The interfacial tension
must be reduced so that air is displaced from the solid surface by liquid.
• Non-ionic surfactants are most commonly used as wetting agents in
pharmaceutical suspension. Non-ionic surfactants having HLB value
between 7-10 are best as wetting agents. High HLB surfactants act as
foaming agents. The concentration used is less than 0.5 %. A high amount
of surfactant causes solubilization of drug particles and causes stability
problem.
• Ionic surfactants are not generally used because they are not compatible
with many adjuvant and causes change in pH.
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• Surfactants
• Surfactants decrease the interfacial tension between drug
particles and liquid and thus liquid is penetrated in the pores of
drug particle displacing air from them and thus ensures wetting.
• Surfactants in optimum concentration facilitate dispersion of
particles. Generally we use non-ionic surfactants but ionic
surfactants can also be used depending upon certain
conditions.
• Disadvantages of surfactants are that they have foaming
tendencies.
• Further they are bitter in taste. Some surfactants such as
polysorbate 80 interact with preservatives such as methyl
paraben and reduce antimicrobial activity.
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• All surfactants are bitter except Pluronics and
Poloxamers.
• Polysorbate 80 is most widely used surfactant both for
parenteral and oral suspension formulation.
• Polysorbate 80 is also adsorbed on drug particle and
decreases its zeta potential. This effect of polysorbate80
stabilizes the suspension.
• Polysorbate 80 stabilized suspensions through steric
mechanism. At low concentration of polysorbate 80,only
partial stabilization of suspension was observed.
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• In absence of polysorbate 80, difficulty was observed in redispersion of sedimented particles.
• Polysorbate 80 is most widely used due to its following
advantages
• It is non-ionic so no change in pH of medium
• No toxicity.
• Safe for internal use.
• Less foaming tendencies however it should be used at
concentration less than 0.5%.
• Compatible with most of the adjuvant.
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Hydrophilic Colloids
• Hydrophilic colloids coat hydrophobic drug particles
in one or more than one layer. This will provide
hydrophillicity to drug particles and facilitate
wetting.
• They cause deflocculation of suspension because
force of attraction is declined. e.g. acacia,
tragacanth,
alginates,
guar gum, pectin, gelatin, wool fat, egg yolk,
bentonite, Veegum, Methylcellulose etc.
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• Solvents
• The most commonly used solvents used are alcohol,
glycerin, polyethylene glycol and polypropylene glycol.
• The mechanism by which they provide wetting is that they
are miscible with water and reduce liquid air interfacial
tension. Liquid penetrates in individual particle and facilitates
wetting.
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• Quality Control of Suspensions
The following tests are carried out in the final quality control
of suspension:
• Appearance Color, odor and taste
• Physical characteristics such as particle size determination
and microscopic photography for crystal growth
• Sedimentation rate and
• Zeta Potential measurement
• Sedimentation volume
• Redispersibility and Centrifugation tests
• Rheological measurement
• Stress test
pH
• Freeze-Thaw temperature cycling
• Compatibility with container and cap liner
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• Ideal Requirements of Packaging Material
• It should be inert.
• It should effectively preserve the product from light, air, and
other contamination through shelf life.
• It should be cheap.
• It should effectively deliver the product without any difficulty.
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